Biomarkers of atherosclerosis and the potential of MRI for the diagnosis of vulnerable plaque.

Atherosclerosis is a chronic inflammatory vascular disease. As it is an inflammation process, many cellular and molecular events are involved at each step of the progression of atherosclerosis from an early fatty streak lesion to a highly dangerous rupture-prone plaque. Magnetic resonance imaging (MRI) is a well-established diagnostic tool for many kinds of chronic inflammation in various systems and organs, and recent improvements in spatial resolution and contrast strategies make it a promising technique for the characterization of inflammatory vessel walls. The first part of this review will briefly introduce the main cellular and molecular processes involved in atherosclerotic lesions; the second part will focus on the use of high-resolution MRI and present-generation contrast agents for plaque characterization; and the third part will present some recent and ongoing cellular and molecular MRI studies of atherosclerosis

Mesure sélective des temps de relaxation T2 des lipides intra et extramyocytaires chez le rat Zucker à 7 teslas

articl

In vivo biodistribution and biological impact of injected carbon nanotubes using magnetic resonance techniques

International audienceSingle-walled carbon nanotubes (SWCNT) hold promise for applications as contrast agents and target delivery carriers in the field of nanomedicine. When administered in vivo, their biodistribution and pharmacological profile needs to be fully characterized. The tissue distribution of carbon nanotubes and their potential impact on metabolism depend on their shape, coating, and metallic impurities. Because standard radiolabeled or fluorescentlylabeled pharmaceuticals are not well suited for long-term in vivo follow-up of carbon nanotubes, alternative methods are required

Measurement of nonlinear pO 2 decay in mouse lungs using 3 He-MRI

ABSTRACT: Spatial and temporal variations in oxygen partial pressure ( pO 2 ) during breath-hold can be exploited to obtain important regional parameters of lung function. In the course of apnea, the oxygen concentration is known to decay exponentially. Therefore, the initial pO 2 ( p 0 ) can be used to represent local ventilation, and the oxygen depletion time constant can characterize perfusion. The protocol, based on a nonlinear model of pO 2 decay, was validated in six healthy mice. Parametric maps of p 0 and oxygen depletion time constant were obtained for pure He/air mixture, in agreement with physiology

Clinical Imaging of Choroid Plexus in Health and in Brain Disorders: A Mini-Review

The choroid plexuses (ChPs) perform indispensable functions for the development, maintenance and functioning of the brain. Although they have gained considerable interest in the last years, their involvement in brain disorders is still largely unknown, notably because their deep location inside the brain hampers non-invasive investigations. Imaging tools have become instrumental to the diagnosis and pathophysiological study of neurological and neuropsychiatric diseases. This review summarizes the knowledge that has been gathered from the clinical imaging of ChPs in health and brain disorders not related to ChP pathologies. Results are discussed in the light of pre-clinical imaging studies. As seen in this review, to date, most clinical imaging studies of ChPs have used disease-free human subjects to demonstrate the value of different imaging biomarkers (ChP size, perfusion/permeability, glucose metabolism, inflammation), sometimes combined with the study of normal aging. Although very few studies have actually tested the value of ChP imaging biomarkers in patients with brain disorders, these pioneer studies identified ChP changes that are promising data for a better understanding and follow-up of diseases such as schizophrenia, epilepsy and Alzheimer’s disease. Imaging of immune cell trafficking at the ChPs has remained limited to pre-clinical studies so far but has the potential to be translated in patients for example using MRI coupled with the injection of iron oxide nanoparticles. Future investigations should aim at confirming and extending these findings and at developing translational molecular imaging tools for bridging the gap between basic molecular and cellular neuroscience and clinical research

Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy

Microglial phagocytosis of apoptotic debris prevents buildup damage of neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse and preclinical monkey models of stroke (macaques and marmosets) by transient occlusion of the medial cerebral artery (tMCAo). By analyzing recently published bulk and single cell RNA sequencing databases, we show that the phagocytosis dysfunction was not explained by transcriptional changes. In contrast, we demonstrate that the impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrient deprivation (OND), which led to reduced process motility, lysosomal exhaustion, and the induction of a protective macroautophagy/autophagy response in microglia. Basal autophagy, in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using pharmacological and transgenic approaches. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro, where it even had a detrimental effect on microglia, suggesting that modulating microglial autophagy to optimal levels may be a hard to achieve goal. Nonetheless, our results show that pharmacological interventions, acting directly on microglia or indirectly on the brain environment, have the potential to recover phagocytosis efficiency in the diseased brain. We propose that phagocytosis is a therapeutic target yet to be explored in stroke and other brain disorders and provide evidence that it can be modulated in vivo using rapamycin.Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; AMBRA1: autophagy/beclin 1 regulator 1; ATG4B: autophagy related 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, autophagy related; CASP3: caspase 3; CBF: cerebral blood flow; CCA: common carotid artery; CCR2: chemokine (C-C motif) receptor 2; CIR: cranial irradiation; Csf1r/v-fms: colony stimulating factor 1 receptor; CX3CR1: chemokine (C-X3-C motif) receptor 1; DAPI: 4',6-diamidino-2-phenylindole; DG: dentate gyrus; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HI: hypoxia-ischemia; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MCA: medial cerebral artery; MTOR: mechanistic target of rapamycin kinase; OND: oxygen and nutrient deprivation; Ph/A coupling: phagocytosis-apoptosis coupling; Ph capacity: phagocytic capacity; Ph index: phagocytic index; SQSTM1: sequestosome 1; RNA-Seq: RNA sequencing; TEM: transmission electron microscopy; tMCAo: transient medial cerebral artery occlusion; ULK1: unc-51 like kinase 1

AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human

Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells

In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs)) by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors), the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC). This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9) or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7). Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response

Physiopathologie cardiovasculaire intégrative : apports et enjeux de l’imagerie moléculaire

Acute cardio and neurovascular ischemic events, namely acute coronary syndrome (ACS) and acute ischemic stroke (AIS), are major public health concerns. Restoring blood flow with mechanical endovascular treatment is systematic for ACS and is revolutionizing stroke management. Reestablishing blood supply is the first line of treatment but secondary ischemia-reperfusion damages are frequent and have a major impact on patient prognosis. Yet, there is no available therapy and the pathophysiological mechanisms and their spatio-temporal evolution are still incompletely understood. Among them, inflammation is a key player but with uncertain outcome at the individual level as it can be either beneficial or deleterious. In this context, what are the future translational approaches for diagnosis and therapy ? Today, who are the actors of this research and how can we train the future specialists ?La prise en charge des accidents vasculaires ischémiques cardiaques (syndromes coronariens aigus ou SCA) et cérébraux (AVC) est un enjeu de santé publique majeur. Pour restaurer le flux sanguin, le traitement mécanique endovasculaire est systématique pour le SCA, et révolutionne actuellement le traitement de l’AVC. Le rétablissement de l’apport sanguin est la première ligne d’action thérapeutique, mais des dégâts secondaires à l’épisode d’ischémie-reperfusion interviennent, qui mettent en jeu le pronostic des patients. Aucun traitement efficace n’existe et leurs mécanismes physiopathologiques comme leur évolution spatio-temporelle sont encore mal circonscrits. Parmi ceux-ci, la réaction inflammatoire est un acteur clé, mais nul à ce jour ne peut en prédire l’issue tant son rôle peut se révéler à l’échelle individuelle bénéfique ou délétère. Dans ce contexte, quelles en seront les approches translationnelles diagnostiques et thérapeutiques ? Aujourd’hui, quels sont les acteurs de ces avancées médicales et comment former ceux de demain ?Canet-Soulas Emmanuelle. Physiopathologie cardiovasculaire intégrative : apports et enjeux de l’imagerie moléculaire. In: Bulletin de l'Académie Vétérinaire de France tome 173, 2020. pp. 185-191

Développements méthodologiques pour l imagerie moléculaire dans le système cardiovasculaire et les noyaux polarisés par Résonance Magnétique Nucléaire

The research in Magnetic Resonance Imaging combining the proton molecular imaging and the hyperpolarized gases (helium-3) imaging is a promising way in the field of the cardiovascular and lung applications. In this context, the subjects of this thesis were to develop the instrumentations and to set up sequences and MR protocols dedicated to the small animal (mice) imaging for non-invasive longitudinal studies of the chronic cardiovascular and lung pathologies. The first chapter is dedicated to the vascular pathologies and the state of art of the knowledge of the MR contrast agents in cardiovascular and lung imaging. The second chapter is dedicated to the molecular imaging of the atherosclerosis plaque to evaluate new contrast agents: 1) non-specific, ex-vivo with a multi-spectral analysis of the atherosclerosis plaque components on human coronary arteries. 2) Specific, to asses the arterial wall inflammation in-vivo in ApoE-/- mice by targeting P-selectin (adhesion molecule expressed in an early stage of the pathology and atherothrombosis). In the third chapter, the real-time cardio-respiratory gating is described which was developed: 1) to study contrast agents of the atherosclerosis plaque in mice at the level of the aortic root and the carotids origin where atherosclerosis predominantly develops. 2) to enable non invasive evaluation of cardiac modifications induced by endurance exercise training in mice. The fourth chapter is dedicated to the pulmonary pathologies and the MRI with the hyperpolarized helium-3 to set up the ventilation lung imaging protocol under spontaneous mouse breathing conditions with fast MR sequences. The administration of the gas was accomplished by a mask allowing a non-invasive approach which is adapted to the longitudinal studies in mouseLYON1-BU.Sciences (692662101) / SudocSudocFranceF